Traumatic brain injury (TBI), the leading cause of death in children and young adults [1-6], leaves many patients (1.5 million annually in the US) with substantial motor disabilities and cognitive impairments [1-4, 6]. TBI represents a significant socioeconomic burden [2, 7-9]. In 2000 civilian TBI patients incurred over $60 billion in medical costs [3, 4, 10, 11]. Furthermore, it is estimated that more than 300,000 Iraq and Afghanistan war veterans have sustained mild traumatic brain injury (mTBIs) from blast waves of wartime improvised explosive devices (20% of 1.6 million) [12, 13]. Therefore, mTBI is a serious public health problem. At present, there is no effective treatment for these TBI-associated disorders. Thus, the development of therapeutic approaches to treat these disorders following TBI would be of enormous clinical, social, and economic benefit. Recently research has identified neural stem/progenitor cells (NSCs) in the adult brain [14-17]. New neurons are continuously generated from NSCs throughout adulthood [18]. These adult-born new neurons are a potential resource for repairing damages in the brain following TBI. In addition, these findings suggest that innate repair and/or plasticity mechanisms exit in the adult brain. However, these innate processes are often unsuccessful, and additional interventions are required to increase the innate plasticity for successfully repairing the damaged brain following TBI. Recently, it has been shown that physical exercise enhanced neurogenesis in the adult hippocampus, and moderately improved its functional performance following TBI [19-21]. This finding suggests that physical exercise-enhanced neurogenesis might be induced in patients following TBI. However, so far exercise-enhanced functional improvement have proven to be moderate, and several questions still remain: 1) Does physical exercise increase NSC proliferation or/and promote newborn neuron survival?;2) What are the molecular and cellular mechanisms that regulate exercise-enhanced neurogenesis?;3) Does exercise-enhanced neurogenesis lead to behavioral improvements in patients following TBI?;and 4) How can this effect be increased to further boost neurogenesis and to potentially greatly improve the behaviorof TBI patients? To address these questions, this proposal will investigate the molecular and cellular mechanisms that regulate exercise-enhanced neurogenesis, and use the molecules identified in this study to further increase exercise-enhanced neurogenesis in the adult hippocampus following TBI. Completion of these studies will not only provide insights into the molecular and cellular mechanisms mediating exercise- enhanced neurogenesis, but also may provide a potential approach to increase neurogenesis and facilitate functional recovery following TBI. PUBLIC HEALTH RELEVANCE: Traumatic brain injury (TBI) is the leading cause of death in children and young adults, and represents a significant socioeconomic burden. It leaves many patients with substantial cognitive impairments and epilepsy. Currently there is no effective treatment for these disorders. This proposal aims to investigate the molecular and cellular mechanisms underlying exercise-enhanced neurogenesis in the hippocampus following TBI, and to potentially find a novel approach to augment exercise-enhanced neurogenesis for functional recovery of patients following TBI.